In general terms, the main research conducted in this proposal is directed towards a better understanding of the action of narcotic analgesics and the development of tolerance and physical dependence to these drugs. The proposal will cover four general areas of opioid research: 1) opiate analgesia, tolerance and physical dependence; 2) opioid receptor pharmacology; 3) interaction studies and 4) opioid receptor probes. More specifically the proposal concerns the following aspects. a) Changes in mu-opioid receptors in the brain with the development of opiate tolerance and dependence. b) Changes in opioid receptors in the spinal cord with the development of opiate tolerance and dependence. c) Reinitiation of physical dependence after prolonged opiate withdrawal and consequent changes in opioid receptors. d) Pharmacology of binaltorphimine (BNI) and nor-BNI, two highly selective kappa-opioid receptor antagonists. e) Pharmacological characterization of opioid receptors in vivo using highly selective antagonists such as beta-FNA, BNI and ICI 174864. f) Nicotine-opiate interaction and the mechanism of nicotine- induced antinociception. g) Pharmacological consequences of kappa opioid receptor interaction. h) Development of highly selective opioid antagonists for the various opioid receptor types and subtypes.